Small Hero with Great Powers: Vaccinia Virus E3 Protein and Evasion of the Type I IFN Response

Mateusz Szczerba, Sambhavi Subramanian, Kelly Trainor, Megan McCaughan, Karen V. Kibler, Bertram L. Jacobs

Research output: Contribution to journalReview articlepeer-review

9 Scopus citations


Poxviridae have developed a plethora of strategies to evade innate and adaptive immunity. In this review, we focused on the vaccinia virus E3 protein, encoded by the E3L gene. E3 is present within the Chordopoxvirinae subfamily (with the exception of the avipoxviruses and molluscum contagiosum virus) and displays pleiotropic effects on the innate immune system. Initial studies identified E3 as a double-stranded RNA (dsRNA)-binding protein (through its C terminus), able to inhibit the activation of protein kinase dependent on RNA (PKR) and the 2 5-oligoadenylate synthetase (OAS)/RNase L pathway, rendering E3 a protein counteracting the type I interferon (IFN) system. In recent years, N-terminal mutants of E3 unable to bind to Z-form nucleic acids have been shown to induce the cellular death pathway necroptosis. This pathway was dependent on host IFN-inducible Z-DNA-binding protein 1 (ZBP1); full-length E3 is able to inhibit ZBP1-mediated necroptosis. Binding to what was identified as Z-RNA has emerged as a novel mechanism of counteracting the type I IFN system and has broadened our understanding of innate immunity against viral infections. This article gives an overview of the studies leading to our understanding of the vaccinia virus E3 protein function and its involvement in viral pathogenesis. Furthermore, a short summary of other viral systems is provided.

Original languageEnglish (US)
Article number235
Issue number2
StatePublished - Feb 2022


  • Host range
  • Innate immunity
  • Interferon
  • Necroptosis
  • PKR
  • Pathogenesis
  • Vaccinia virus
  • Viral immune evasion
  • Z-RNA
  • ZBP1

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)


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